Discordant Twin Pairs Research Articles

Genetic and environmental risk factors for asthma: a cotwin-control study.

In complex diseases of genetic etiology such as asthma and atopy, it is difficult to differentiate causes of disease from consequences, and quantitate the importance of such causative factors. We examined possible risk factors for the development of wheezing and bronchial hyperresponsiveness in a cotwin-control study nested within a larger community-based twin-family study. In 62 monozygotic (MZ) twin pairs discordant for a history of wheezing, skin prick test to house dust extract was the most important discriminator, followed by sensitization to cat and cockroach allergens. In contrast, 62 dizygotic (DZ) discordant twin pairs differed additionally in sensitization to grass pollens and fungi. Markers such as serum haptoglobin, serum magnesium, and alpha-1-antitrypsin levels did not differ significantly between discordant twins. This MZ/DZ difference suggests that pollen allergy in asthmatics is more an epiphenomenon due to a genetic correlation between asthma and the allergic diathesis, whereas indoor allergens are likely to be direct environmental causes of asthma.

Apolipoprotein E type epsilon4 allele, heritability and age at onset in twins with Alzheimer disease and vascular dementia.

The apolipoprotein E (APOE) epsilon4 allele is a risk factor in Alzheimer disease (AD), but not in vascular dementia (VaD). We have investigated whether the epsilon4 allele is more common in twin pairs concordant for AD, compared with those discordant for AD, and whether the epsilon4 allele is more common in AD twins than in VaD twins. In addition, we have investigated the relationship of the epsilon4 allele and the age at onset in AD and VaD. APOE genotype was analysed in 29 senile demented twin pairs. The epsilon4 allele was associated with AD and not with VaD. However, there was no difference in the frequency of the APOE epsilon4 allele in concordant (33.3%) and discordant (31.3%) AD dizygotic twin pairs. Age at onset in AD was significantly lower in epsilon4 homozygotes than in individuals with one or no copies of epsilon4 (62.4 vs. 73.5, p<0.01). In concordant AD twin pairs, the epsilon4 allele frequency was somewhat higher in the twins with earlier onset (41.7% vs. 25%), but the difference was not statistically significant. In the VaD group the age at onset was not significantly different between individuals with or without epsilon4 in their genotypes.

Lifetime exercise and disk degeneration: an MRI study of monozygotic twins.

Participation in some competitive sports has been shown to increase disk degeneration; however, the long-term effects of recreational physical activities are unclear. We investigated the effects of endurance exercise and power sports on disk degeneration in monozygotic male twins with contrasting lifetime exercise histories. The effects of endurance exercise were studied in 22 discordant twin pairs (mean lifetime frequencies of 3.9 vs 1.1 times/wk), and the effects of power sports were investigated in 12 discordant pairs (2,300 vs 200 h of weightlifting). The age range of the twins was from 35 to 69 yr. No differences in MRI findings between co-twins discordant for endurance exercise were found at any of the spinal regions. Subjects with more power sport involvement had greater disk degeneration in the T6-T12 region (P < 0.03), but similar findings were not present in the lumbar spine. Controlling for recalled back injuries, occupational loading, smoking, and driving did not significantly affect the results. No signs of beneficial or harmful effects of lifetime endurance exercise on disk degeneration were seen. Increased power sport participation was associated with slightly greater disk degeneration in the lower thoracic spine, but not in the lumbar spine.

Sonographic examination does not predict twin growth discordance accurately

To assess the accuracy of estimating birth weight among twins with discordancy (intra-pair difference in actual birth weight of more than 25%) and to determine the relative accuracy of an intra-pair difference in abdominal circumference (delta AC) of 20 mm or more or in estimated fetal weight (delta EFW) of 25% or more for the identification of discordant growth in twins. Over a 6-year period, we identified all non-anomalous twin pairs with gestational ages greater than 23 weeks and sonographic examinations within 3 weeks of birth. Ultrasonographic biometry of both twins included AC, head circumference, and femur length; these indices were used to estimate fetal weight by Hadlock's formula. Likelihood ratios, receiver-operating characteristic curves, and prediction limits were applied to assess the accuracy of the two diagnostic methods to predict an abnormal outcome. A total of 242 twin pairs were studied. The mean gestational age among the 21 twins with abnormal growth (30.6 +/- 4.6 weeks) was significantly less than among the 221 twins with normal growth (33.2 +/- 4.0 weeks) (P < .005). The biometric measurements of fetal parts, sonographic estimate of fetal weight, and actual birth weight for both fetuses were significantly less for discordant twin pairs (P < .05). The accuracy of predicting birth weight, as determined by mean error and percentage of the estimate within 10% of the actual weight, was similar between the groups. Receiver-operating characteristic curves showed that both diagnostic tests yielded areas under the two curves not significantly different from the area under the nondiagnostic line (P > .05). Most important, prediction limit calculations indicated that a 90% certainty that the actual birth weight discordance was at least 25% was achievable only if delta AC was 172 mm or greater or delta EFW was 112% or more. The most popular current methods (difference in AC or EFW) for predicting discordant growth in twin gestations have limited accuracy when held to a standard for discordance that requires a birth weight difference of at least 25%.

X-Chromosome Inactivation in Monozygotic Twins with Systemic Lupus Erythematosus

The hypothesis that a low concordance rate in monozygotic (MZ) twins with systemic lupus erythematosus (SLE) may be accounted for by differences in X-chromosome inactivation was examined. Five MZ twin pairs, four discordant and one concordant, were recruited, zygosity confirmed by DNA fingerprinting, and their pattern of X-chromosome inactivation in DNA samples prepared from peripheral blood and buccal cells were examined. X-chromosome inactivation was assessed by the methylation status of the CpG region near trinucleotide repeats in exon 1 of the androgen receptor gene on X-chromosome after digestion with the methylation-sensitive enzyme Hpall or Hhal and PCR amplification. X-chromosome inactivation patterns were found to be the same between affected and non-affected twins in all four discordant twin pairs, with random patterns in two pairs and skewed patterns in the others. The concordant twins demonstrated the same random patterns. X-chromosome inactivation was also examined from buccal smear DNA and shown to have the same pattern as that noted from peripheral blood DNA in one informative twin pair. Differences in X-chromosome inactivation patterns were not observed in these five MZ twin pairs. The results could not support the hypothesis that differences in X-chromosome inactivation is the mechanism accounting for the low concordance rate noted in MZ twins with SLE.

Temperament development to 30 months of age in discordant twin pairs.

Twins within pairs often have different weights at birth. A difference of 15% or greater is defined as discordance for weight and is considered to place one or both infants at risk. Temperature differences had been found in the neonatal period for fullterm discordant cotwins, but not for preterm discordant cotwins, suggesting that continued gestation for discordant twins was a risk variable for early behavior. 30 pairs of fullterm and 17 pairs of preterm discordant pairs were followed at 6, 9, 12, 18, 24, and 30 months of age. Group differences were observed for the longitudinal maintenance of cotwin discordance in physical measures, with preterm cotwins becoming more like each other. In laboratory assessments, temperament differences no longer were observed between the larger and smaller cotwins. Questionnaires indicated that mothers generally did not differentiate between their larger and smaller cotwin children in temperament ratings, except for ratings of mood for the fullterm pairs. Thus, emotionality was the only temperament dimension that differentiated between the fullterm discordant twins both in the neonatal period and at later ages. In the main, it was concluded that the fullterm discordant twins overcame the adverse in-utero influences on early behavioral development.

The association of antisocial personality symptoms with marijuana abuse/dependence. A monozygotic co-twin control study.

This study examines the association of symptoms of lifetime antisocial personality disorder (ASP) with marijuana abuse/dependence in Vietnam-era veteran male monozygotic twin pairs. In 1992, 1,874 monozygotic twin pairs responded to a structured psychiatric interview that obtained data on lifetime history of drug use and ASP. Among randomly selected individuals from each twin pair, 8 of 10 ASP symptoms were significantly more prevalent in persons with a lifetime history of marijuana abuse/dependence compared with those who had never abused any drug (p < .001). Among 99 marijuana discordant twin pairs, however, only two ASP symptoms, "failure to conform to social norms" (odds ratio, 2.8; 95% confidence interval, 1.5 to 5.5) and "reckless regard of own or other's personal safety" (odds ratio, 2.4; 95% confidence interval, 1.0 to 5.4) were significantly increased in marijuana abusing/dependent twins compared with their non-abusing/nondependent twin brother. After adjustment for conduct disorder, alcohol abuse/dependence, and exposure to combat in Vietnam, only "failure to conform to social norms of lawful behavior" (odds ratio, 2.42; 95% confidence interval, 1.12 to 5.21) remained significantly increased in twins with marijuana abuse/dependence.

Reliability and reporting biases for perceived parental history of alcohol-related problems: agreement between twins and differences between discordant pairs.

Previous research suggests that family history of alcoholism assessments may be biased by characteristics of the informant. In this report, the reliability and potential biases in offspring reports of paternal and maternal alcohol-related problems were examined in a large community sample of adult twins. Subjects were volunteer participants in the Australian NH&MRC twin registry. Agreement between twin pairs on reports of paternal and maternal alcohol problems was assessed in 2,657 twin pairs (1,444 female-female pairs, 626 male-male pairs, and 587 female-male pairs). In addition, to detect systematic reporting biases, like-sex twin pairs whose paternal alcohol problems reports disagreed (n = 164) were contrasted on measures of personality, state anxiety and depression, parental rearing, alcoholism, and alcohol use. Twin agreement for parental alcohol-related problems was good, with overall kappas of .66 for paternal and .58 for maternal alcohol problems. When discordant twin pairs were compared, we found that women who reported that their father had alcohol problems were significantly lower on EPQ-R Social Conformity than their twin sister who denied paternal alcohol problems: and there was a trend for men who reported that their father had alcohol problems to be higher in negative perceived parenting from father than their twin brother who denied paternal alcohol problems. Twins discordant for reporting paternal alcohol problems did not, however, differ on the major dimensions of personality, state anxiety and depression, alcoholism, or current alcohol use. The results of this study bolster our confidence in using the family history method to examine characteristics of offspring of alcoholics versus offspring of nonalcoholics on self-reported measures of personality and psychopathology, but suggest that some caution should be exercised when using this method to examine differences in offspring-reported perceptions of parental rearing practices.

Morbidity and mortality of discordant twins up to 34 weeks of gestational age.

The combination of weight discordance and prematurity implies a high perinatal morbidity and mortality for the affected twins. Several pathomechanisms may be responsible for the weight difference in twins including a different genetic growth potential in dizygotic twins, placenta insufficiency in one twin, and chronic feto-fetal transfusion (CFFT). Little is known about neonatal morbidity and mortality of discordant twins. Therefore, a retrospective, case-controlled study on preterm discordant twins up to 34 weeks gestation was carried out. Twenty-seven (27,3%) of 99 twin pairs born in our clinic had a birth weight difference of more than 20%. The control group consisted of 27 non-discordant twins matched for gestational age. Discordant twins showed a significantly higher mortality (19%) than the control twins (2%). Severe intracranial haemorrhage (ICH) and persistent ductus arteriosus Botalli (PDA) were found more often in discordant twins than in the control group. The increased mortality and morbidity of discordant twins compared with concordant twins matched for gestational age indicates that the increased morbidity and mortality of preterm weight discordant twins is not only due to prematurity, but is also related to the discordance itself. Thirteen (48.1%) of the weight discordant twin pairs fulfilled the criteria for CFFT. Twins with CFFT differed significantly from controls with respect to the incidence of mortality and the rate of severe ICH, PDA, and the necessity of postnatal cardiopulmonary resuscitation. By contrast, no significant differences were found between discordant twins without CFFT and controls. Thus, CFFT appears to be a major contributing factor for increased mortality and morbidity of weight discordant twins. Intra-twin pair analysis revealed a higher rate of postnatal hypoglycaemia in the smaller twins only, probably caused by insufficient glycogen storage due to intra-uterine malnutrition. Mortality was the same for both the larger and the smaller twins. It may be concluded that neonatal outcome of smaller twins who have survived intra-uterine malnutrition is the same as in larger twins. Intra-twin pair analysis in twins with CFFT revealed no significant differences except for a higher rate of ICH grade 2-4 in the larger twins which might be explained by hypervolaemia of the recipient. Morbidity and mortality of weight discordant twins are increased. CFFT appears to be a major contributing factor for the increased mortality and morbidity. Postnatal mortality was the same in acceptor and donor; however, the acceptor had a higher postnatal morbidity.

Normal personality characteristics in identical twins discordant for schizophrenia.

The authors examined normal personality characteristics of monozygotic (MZ) twins discordant for schizophrenia. Twenty pairs of discordant twins were analyzed; 11 pairs of MZ twins concordant for schizophrenia served as a comparison group. Personality was assessed using the Multidimensional Personality Questionnaire (MPQ; A. Tellegen, 1995). Among discordant twin pairs, twins with schizophrenia were more deviant than normal co-twins on all but 4 of the MPQ's scales. Analysis of MZ twin correlations among the discordant twin pairs revealed substantial erosion of personality similarity as compared to normal individuals, although a cluster of scales related to Constraint/Psychoticism showed significant correlations. The results highlight striking personality divergence related to nonshared environmental influences. It is not possible to determine the point at which the twins diverged, although previous findings from this sample suggest that the observed personality differences may reflect effects of schizophrenia on normal personality.

Delayed onset of Alzheimer's disease with nonsteroidal anti-inflammatory and histamine H2 blocking drugs

Factors that modify onset of Alzheimer's disease (AD) may be revealed by comparing environmental exposures in affected and unaffected members of discordant twin pairs or sibships. Among siblings at high risk of AD, sustained use of nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with delayed onset and reduced risk of AD. After adjustment for use of NSAIDs, there was minimal effect on onset with reported history of any of three common illnesses (arthritis, diabetes, or acid-peptic disease). However, independent of exposure to NSAIDs, onset was unexpectedly delayed in those reporting extended use of histamine H2 blocking drugs. Randomized clinical trials will be needed to affirm the utility of these drugs for prevention, but the present findings may have implications for pathogenesis: because NSAIDs block the calcium-dependent postsynaptic cascade that induces excitotoxic cell death in NMDA-reactive neurons, and because histamine potentiates such events, excitotoxicity may deserve additional investigation in AD.

'Microgastria-limb reduction' complex with congenital heart disease and twinning

We report a newborn, the second of male twins, with multiple abnormalities, including microphthalmia, a complex cardiovascular malformation, asplenia, anomalous lobation of the lungs, oesophageal atresia, microgastria, intestinal malrotation, anal atresia, multicystic dysplastic kidneys, and reduction defects of the upper extremities. These defects fit into the so-called 'microgastria-limb reduction' complex. Two of twelve previously reported patients with this complex were from discordant twin pairs. The occurrence of twinning in three out of 13 cases suggests that the origin of the 'microgastria-limb reduction' complex may be related to the process of twinning itself.

Non‐random X chromosome inactivation in an affected twin in a monozygotic twin pair discordant for Wiedemann‐Beckwith syndrome

Wiedemann-Beckwith syndrome (WBS) is a syndrome including exomphalos, macroglossia, and generalized overgrowth. The locus has been assigned to 11p15.5, and genomic imprinting may play a part in the expression of one or more genes involved. Most cases are sporadic. An excess of female monozygotic twins discordant for WBS have been reported, and it has been proposed that this excess could be related to the process of X chromosome inactivation. We have therefore studied X chromosome inactivation in 13-year-old monozygotic twin girls who were discordant for WBS. In addition, both twins had Tourette syndrome. The twins were monochorionic and therefore the result of a late twinning process. This has also been the case in previously reported discordant twin pairs with information on placentation. X chromosome inactivation was determined in DNA from peripheral blood cells by PCR analysis at the androgen receptor locus. The affected twin had a completely skewed X inactivation, where the paternal allele was on the active X chromosome in all cells. The unaffected twin had a moderately skewed X inactivation in the same direction, whereas the mother had a random pattern. Further studies are necessary to establish a possible association between the expression of WBS and X chromosome inactivation.

Normal personality characteristics in identical twins discordant for schizophrenia.

The authors examined normal personality characteristics of monozygotic (MZ) twins discordant for schizophrenia. Twenty pairs of discordant twins were analyzed; 11 pairs of MZ twins concordant for schizophrenia served as a comparison group. Personality was assessed using the Multidimensional Personality Questionnaire (MPQ; A. Tellegen, 1995). Among discordant twin pairs, twins with schizophrenia were more deviant than normal co-twins on all but 4 of the MPQ's scales. Analysis of MZ twin correlations among the discordant twin pairs revealed substantial erosion of personality similarity as compared to normal individuals, although a cluster of scales related to Constraint/Psychoticism showed significant correlations. The results highlight striking personality divergence related to nonshared environmental influences. It is not possible to determine the point at which the twins diverged, although previous findings from this sample suggest that the observed personality differences may reflect effects of schizophrenia on normal personality.

Twin study using mortality data: a new sampling method.

To evaluate the success of a novel approach to twin studies using death discordant twin pairs in a disease of low prevalence. A population study based on all registered deaths at the Office of Population Censuses and Surveys of England and Wales, classified under the ICD code 335.2 (motor neuron disease [MND]) for the period 1979-1989 inclusive. From the above database of 10,872 people, individuals born after 31 December 1899 were traced in the Birth Indices for England & Wales to enable identification of possible twins. In all 131 twin pairs were found and the co-twin details were sent to the National Health Service Central Register (NHS-CR) to enable location of the relevant Family Health Services Authority and thence the co-twin's general practitioner (GP). A letter requesting access was sent to the family practitioners. If given, the co-twin can be approached and interviewed. The search produced: 54 living co-twins; 31 who died as adults; 29 infant deaths; 5 emigrated; 3 incorrectly diagnosed index twins; and 9 untraceable co-twins. Among the adult deaths two concordant pairs were identified. This has created the largest twin population sample worldwide for MND. This new twin study method is clearly viable, and has produced a large unbiased sample compared to that possible using traditional methods. It relies heavily on the accuracy of death certificates and zygosity reporting by living co-twins, but is possibly the only way of collecting twins in rare conditions.

Lower Cognitive Performance in Normal Older Adult Male Twins Carrying the Apolipoprotein E 4 Allele

Given the strong association of the apolipoprotein E (apoE) allele epsilon 4 with late-onset Alzheimer dementia or multi-infarct dementia, we tested whether normal older adult men with at least one epsilon 4 allele demonstrate subclinical changes in cognition and perform more poorly on tests of cognitive function compared with subjects without the epsilon 4 allele. Matched-pair design of normal adult male (average age, 63 years) fraternal twins. Subjects voluntarily participated on an outpatient basis at a research or medical center facility. Members of the National Heart, Lung, and Blood Institute twin panel third examination previously genotyped for apoE. Education-adjusted scores on several neuropsychological tests were compared in twins discordant for the apoE epsilon 4 allele. Subjects with documented cerebrovascular disease were excluded. Among 20 fraternal twin pairs discordant for the presence of epsilon 4, twins with the epsilon 4 allele demonstrated poorer mean performance than their co-twins without the epsilon 4 allele. This relationship was also noted cross-sectionally where age- and education-adjusted scores of 50 individual twin subjects with at least one epsilon 4 allele demonstrated poorer performance compared with 138 individual twins without an epsilon 4 allele. The apoE epsilon 4 allele may be associated with decreased cognitive function in discordant twin pairs. Our results suggest that epsilon 4 may represent a potential marker for accelerated cognitive aging and such individuals may be at greater risk for development of late-onset Alzheimer dementia or multi-infarct dementia.

Difference in susceptibility to teratogenic effects of alcohol in discordant twins exposed to alcohol during the second half of gestation

A pair of discordant twins exposed to heavy maternal alcohol consumption only during the second half of pregnancy is reported. Apparently, differences in susceptibility to the dysmorphogenic influence of ethanol caused 1 twin to be more severely affected than the other. One twin had prenatal growth retardation, neonatal withdrawal symptoms, delay in both motor and cognitive function during the first year of life, slowing of background activity on electroencephalography, and cortical and central brain atrophy on computed tomography. Catch-up growth occurred during the postnatal period for the affected twin. The other twin was normal at the end of the follow-up at age 17 months. It seems that exposure to alcohol during the second half of pregnancy greatly increases the risk for brain damage but not lasting postnatal growth retardation. Minor abnormalities can also be caused during the second half of pregnancy. Genetic factors may have been important in determining the differences in fetal susceptibility to alcohol exposure.

Link between pregnancy complications and minor physical anomalies in monozygotic twins discordant for schizophrenia.

The aim of the current study was to explore the relevancy of early pregnancy complications for the development of minor physical anomalies in monozygotic twins discordant and concordant for schizophrenia. Pregnancy complications and minor physical anomalies were independently assessed in 22 discordant, 10 concordant, and six normal comparison monozygotic twin pairs. Complications occurring during early pregnancy were associated with a higher frequency of minor physical anomalies in the total group and in the discordant twin pairs particularly. While no significant differences in anomaly rates were observed among the discordant, concordant, and normal comparison groups, the discordant ill twins showed a trend toward having more anomalies than their well co-twins. Complications occurring early in pregnancy are relevant for the development of minor physical anomalies and may be of particular importance for the development of these anomalies in twin pairs discordant for schizophrenia.

Decreased levels of soluble amyloid beta-protein precursor are associated with Alzheimer's disease in concordant and discordant monozygous twin pairs.

We conducted immunochemical measurements of soluble amyloid beta-protein precursor (beta PP) in cerebrospinal fluid (CSF) from three monozygous twin pairs. Two of the twin pairs are discordant for Alzheimer's disease and one pair showed concordance for Alzheimer's disease, which was confirmed neuropathologically. All affected individuals displayed substantially lower levels of soluble beta PP in CSF compared with the unaffected individuals. There were no differences in total protein levels in CSF samples from the affected twins compared with those of the unaffected twins. These studies suggest that decreased soluble beta PP in CSF may reflect neuropathological processes in Alzheimer's disease involving beta PP.

Influence of previous exposure to human parvovirus B19 infection in explaining susceptibility to rheumatoid arthritis: an analysis of disease discordant twin pairs.

To assess the association between exposure to parvovirus B19 and susceptibility to rheumatoid arthritis (RA). One hundred and fifty five twin pairs (76 monozygotic (MZ) and 79 dizygotic (DZ)), discordant for RA, were tested for the presence of IgG antiparvovirus antibodies using ELISA. The data obtained were analysed using conditional logistic regression, from which odds ratios and 95% confidence intervals were calculated. Overall, there was no association between exposure to parvovirus and RA (OR = 1.2, 95% CI: 0.7-1.7). However, in two subgroups there was a suggestion of an association. These were: (1) pairs where the affected twin was rheumatoid factor (RF) seronegative (OR = 2.0, 95% CI: 0.9-12.4) and (2) in opposite-sexed twin pairs where the affected twin was female (OR = 3.0, 95% CI: 0.9-11.6). Previous exposure to parvovirus infection did not explain disease susceptibility in both MZ and DZ discordant pairs with rheumatoid arthritis. This infection, however, might be relevant in some subgroups.